Oral administration of ketamine

ABSTRACT

Disclosed are pharmaceutical compositions having a portion of ketamine for intraoral release and another ketamine for gastrointestinal release. The compositions can further include aspirin. The disclosed formulations and related administration approaches improve the bioavailability and efficacy of oral ketamine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of UnitedStates Provisional Application Ser. No. 63/135,126, filed Jan. 8, 2021,63/176,654, filed Apr. 19, 2021, and 63/235,413, filed Aug. 20, 2021,the contents of which are incorporated by reference in their entiretyinto the present disclosure.

BACKGROUND

Acute Pain is one of the most frequent chief complaints and the mainreason for visiting the Emergency Department (ED). The acute pain in theED is largely prevalent across the country with recent literaturedemonstrating that 61-91% of patients are admitted to the ED due to avariety of acute painful syndromes. Musculoskeletal pain (MSK) affectsone out of three adults and it is the most common source of serious longterm pain and physical disability. Furthermore, studies havedemonstrated that the frequency for analgesia for adults who receivedtreatment for musculoskeletal pain in the ED is between 11-29%.

To complicate the issue of MSK pain management even further, the opioidepidemic spanning over 20 years in the USA and claiming over 400,000deaths from unintentional prescription opioid overdose, has forcedhealth care systems and hospitals across the nation to reduce thereliance on opioid analgesics and embrace the utility of non-opioidanalgesia. Several classes of non-opioid analgesics such asacetaminophen, NSAID's (aspirin, ibuprofen, diclofenac) and ketaminehave gained great deal of attention as viable alternatives to opioids inmanagement of acute MSK pain in the ED.

Ketamine is commonly used for anesthesia. It induces a trance-like statewhile providing pain relief, sedation, and memory loss. Other usesinclude sedation in intensive care and treatment of pain and depression.Heart function, breathing, and airway reflexes generally remainfunctional. Common side effects include agitation, confusion, orhallucinations as the medication wears off. Elevated blood pressure andmuscle tremors are also common. Spasms of the larynx may occur, butrelatively infrequently.

Ketamine was discovered in 1962, first tested in humans in 1964, andapproved for use in the United States in 1970. It is on the World HealthOrganization's List of Essential Medicines. It is also used as arecreational drug for its hallucinogenic and dissociative effects.

Ketamine can be absorbed by intravenous, intramuscular, oral, andtopical routes due to both its water and lipid solubilities. In medicalsettings, ketamine is usually injected intravenously or intramuscularly.Oral ketamine, however, is easily broken down by bile acids, and hencehas a low bioavailability. Bioavailability through the oral routereaches 17 to 29%. By contrast, bioavailability through intramuscularinjection is about 93%.

The onset of action of ketamine is seconds intravenously and 1 to 5minutes intramuscularly, but 15 to 30 minutes orally. Moreover, maximalconcentrations of ketamine are reached in 1 to 3 minutes intravenously,and 5 to 15 minutes intramuscularly, but 30 minutes orally.

There is a need to develop oral formulations for ketamine with improvedbioavailability and faster action.

SUMMARY

It has been discovered that oral administration of ketamine achieved aremarkably higher bioavailability when the ketamine was partiallyreleased intraorally and delivered transmucosally and partially releasedthrough the gastrointestinal (GI) track, as compared to intraoral or GIrelease alone. Further, certain desired effects of ketamine, such aspain (acute pain, acute on chronic pain, chronic pain) reduction,suppression of depression, reduction of fatigue (e.g., multiplesclerosis fatigue), reduction of suicidality, treatment ofasthma/reactive airway, treatment of cannabinoid hyperemesis syndromeexacerbations, and treatment of Alzheimer's/dementia can be furtherenhanced by co-administration with aspirin which meanwhile can reducethe undesired effects of ketamine, including its sedation effect andaddiction potential.

In accordance with one embodiment of the present disclosure, therefore,provided is a pharmaceutical composition comprising a first portioncomprising a first amount of ketamine, and a second portion comprising asecond amount of ketamine, wherein, upon oral administration to asubject, the first portion disintegrates or dissolves intraorallysubstantively providing rapid release of the ketamine of the firstportion, and the second portion is substantially more difficult than thefirst portion to disintegrate or dissolve intraorally but is ingestibleand releasable in the gastrointestinal track of the subject.

The pharmaceutical composition can be in the form of a tablet orcapsule. In one aspect, the second portion is enclosed within the firstportion. In one aspect, the first portion is chewable. In anotheraspect, the first portion is in the form of molded triturate.

In one aspect, the second portion is compressed. In another aspect, thehardness of the second portion is at least about 10 kilopascal (kp). Inyet another aspect, the second portion further comprises apharmaceutically acceptable flavoring agent not present in the firstportion.

In any of the above embodiments, the pharmaceutical composition furthercomprises a third portion that comprises an effective amount of aspirin.In still another aspect, the aspirin is part of the first portion or thesecond portion. In one aspect, the aspirin is present in both the firstportion and the second portion.

Another embodiment of the present disclosure provides a method ofadministering ketamine to a subject, comprising administering to thesubject (a) a first composition comprising a first amount of ketamineand (b) a second composition comprising a second amount of ketamine,wherein the first composition disintegrates or dissolves intraorallysubstantively providing rapid release of the ketamine of the firstportion, and the second composition is ingested and released in thegastrointestinal track of the subject.

In one aspect of such a method, the administration is within 30 minutesfollowing a meal. In another aspect, the administration is accompaniedby oral administration of an acidic drink which can assist transmucosalabsorption of the first ketamine composition.

Also provided is a method of administering ketamine to a subject withimproved bioavailability, comprising administering to the subject afirst composition comprising a first amount of ketamine and a secondcomposition comprising a second amount of ketamine, wherein the firstcomposition disintegrates or dissolves intraorally within 10 minutespermitting rapid release of the ketamine in the first composition, andthe second composition is ingested and released in the gastrointestinaltrack of the subject.

Either of these methods can further comprise administering to thesubject an effective amount of aspirin, along with the first compositionor the second composition, or both.

Another embodiment provides a pharmaceutical composition comprisingketamine and aspirin. In some embodiments, the composition comprises afirst portion comprising a first amount of the aspirin, and a secondportion comprising a second amount of the aspirin, wherein, upon oraladministration to a subject, the first portion disintegrates ordissolves intraorally providing rapid release of the aspirin of thefirst portion, and the second portion is substantially more difficultthan the first portion to disintegrate or dissolve intraorally but isingestible and releasable in the gastrointestinal track of the subject.

Also provided is a method of administering ketamine to a subject,comprising administering to the subject ketamine and aspirin. In someembodiments, the aspirin is administered as (a) a first compositioncomprising a first amount of aspirin and (b) a second compositioncomprising a second amount of aspirin, wherein the first compositiondisintegrates or dissolves intraorally providing rapid release of theaspirin of the first portion, and the second composition is ingested andreleased in the gastrointestinal track of the subject.

In another embodiment, provided is a pharmaceutical compositioncomprising ketamine and a glutamate ionotropic receptor NMDA typesubunit 2A (GRIN2A) modulator. Examples include aspirin, nicotine,propofol, melatonin and GQ1b.

Also provided is a method of administering ketamine to a subject,comprising administering to the subject ketamine and a GRIN2A modulator.

Still further provided is a GRIN2A modulator for use in enhancing theefficacy of pain relief, or reducing the side effects of ketamine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 compares the pain reduction efficacies of different treatments.

FIG. 2 compares the sedation side effects of different treatments.

FIG. 3 compares the disassociation side effects of different treatments.

FIG. 4 compares the moderate/severe adverse events experienced inpatients of different groups.

FIG. 5 compares the SERSDA2+ adverse events experienced in patients ofdifferent groups.

FIG. 6 compares the pain reduction in patients of different groups.

FIG. 7 compares the pain reduction in patients of different groups.

FIG. 8 compares the SERSDA2+ adverse events experienced in patients ofdifferent groups.

FIG. 9 compares the pain reduction in patients of different groups.

FIG. 10 compares time to reach 50% pain reduction in patients ofdifferent groups.

DETAILED DESCRIPTION

The present disclosure provides pharmaceutical compositions for oraladministration of ketamine.

A. Definitions

Unless defined otherwise, the terms used herein are intended to havetheir ordinary meaning in the art.

All numerical designations, e.g., pH, temperature, time, concentration,and weight, including ranges, are approximations that typically may bevaried (+) or (−) by increments of 0.1, 1.0, 10.0, or 100.0 asappropriate. It is to be understood, although not always explicitlystated, that all numerical designations are preceded by the term“about”.

“About” will be understood by persons of ordinary skill in the art andwill vary to some extent on the context in which the term is used. Ifthere are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” willmean up to plus or minus 10%, or 5%, or 2% or 1% or 0.5% of theparticular term.

As used herein, the term “comprising” means any recited elements arenecessarily included and other elements may optionally be included.“Consisting essentially of” means any recited elements are necessarilyincluded, elements that would materially affect the basic and novelcharacteristics of the listed elements are excluded, and other elementsmay optionally be included. “Consisting of” means that all elementsother than those listed are excluded. Embodiments defined by each ofthese terms are within the scope of this invention.

As used in the specification and claims, the singular form “a”, “an”,and “the” includes plural references unless the context clearly dictatesotherwise.

“Administering” or “administration of” a drug to a patient (andgrammatical equivalents of this phrase) refers to direct administration,which may be administration to a patient by a medical professional ormay be self-administration, and/or indirect administration, which may bethe act of prescribing a drug. For example, a physician who instructs apatient to self-administer a drug and/or provides a patient with aprescription for a drug is administering the drug to the patient.

As used herein, “compressed” dosage form (e.g., “compressed portion”),refers to a dosage form comprising a compressed powder. For example, acompressed portion may be formed using a rotary tablet press or othersimilar machinery known to one of skill in the art.

As used here, “disintegrates or dissolves intraorally” refers to that amajority of a composition or a portion of a composition, such as atablet or a capsule, breaks apart into smaller particles intraorally.The majority, in one aspect, means at least about 50%, or alternativelyat about 60%, or 70%, or 80%, or 90%, or 95%, or 98%, or 99%.

As used herein, “bilayer” compressed dosage form (e.g., “bilayertablet”) refers to a single compressed dosage form comprising twolayers. A bilayer compressed dosage form can be made in a singlecompression step. Likewise, a “trilayer” compressed dosage form (e.g.,“trilayer tablet”) refers to a single compressed dosage form comprisingthree layers.

As used herein, “wet granulation” refers to a process known in thepharmaceutical arts that involves forming granules by the addition of aliquid, such as purified water, alcohol, or a binder solution.

“Controlled release form” refers to a formulation in which the aspirinis included within a matrix, which matrix can be either insoluble,soluble, or partly soluble. Controlled release matrix formulations ofthe insoluble type are also referred to as insoluble polymer matrices,swellable matrices, or lipid matrices depending on the components thatmake up the matrix. Controlled release matrix formulations of thesoluble type are also referred to as hydrophilic colloid matrices,erodible matrices, or reservoir systems. Controlled release formulationsof the present disclosure refer to formulations comprising an insolublematrix, a soluble matrix or a combination of insoluble and solublematrices in which the rate of release is slower than that of an uncoatednon-matrix or immediate release formulations or uncoated normal releasematrix formulations. Controlled release formulations can be coated witha control releasing coat to further slow the release of aspirin from thecontrolled release matrix formulation. Such coated controlled releasematrix formulations can exhibit modified-release, controlled-release,sustained-release, extended-release, prolonged-release, delayed-release,or combinations thereof, of aspirin. Examples of controlled releaseforms of aspirin include Slo-Aspirin® available from Upsher SmithLaboratories, Inc. (Maple Grove, Minn.).

“Controlled release coat” refers to a functional coat which can, forexample, include at least one pH independent or pH dependent (such asfor example enteric or reverse enteric types) polymer, soluble orinsoluble polymer, lipids or lipidic materials, or combinations thereof,which, when applied onto a formulation can slow (for example, whenapplied to an immediate release formulation or a normal release matrixformulation), further slow (for example when applied to a controlledrelease matrix formulation), or modify the rate of release of aspirin.

“Excipient” refers to a pharmacologically inactive substance used withthe active agents or drugs of a medication or a formulation. Excipientsare also sometimes used to bulk up formulations that contain very potentactive ingredients, to allow for convenient and accurate dosage. Inaddition to their use in the unit dose forms, excipients can be used inthe manufacturing process to aid in the handling of the active substanceconcerned. Depending on the route of administration, and form ofmedication, different excipients may be used. Examples of an excipientincludes, without limitation, one or more of the following: an additive,an anti-foaming agent, a binder, a chemical stabilizer, a coloringagent, a diluent, a disintegrating agent, an emulsifying agent, afiller, a flavoring agents, a glidant, a lubricant, a pH modifier, aplasticizer, a solubilizer, a swelling enhancer, a spheronization aid, asolubility enhancer, or a suspending agent.

“Immediate release formulation” refers to a formulation from which thedrug is released without any substantial delay and substantially atonce.

“Patient” or “subject” refers to mammals, including humans and animals,such as simians, cattle, horses, dogs, cats, and rodents having the needto take aspirin.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts derived from a variety of organic and inorganic counter ions wellknown in the art that include, by way of example only, sodium,potassium, calcium, magnesium, ammonium, and tetraalkylammonium, andwhen the molecule contains a basic functionality, salts of organic orinorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, and oxalate. Suitable salts include thosedescribed in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook ofPharmaceutical Salts Properties, Selection, and Use, 2002, incorporatedherein by reference.

“Plasticizer” refers to a compound capable of plasticizing or softeninga polymer or a binder. Plasticizers can broaden the average molecularweight of a polymer in which they are included thereby lowering itsglass transition temperature or softening point. Plasticizers also canreduce the viscosity of a polymer. The use of plasticizers is optional,but they can be included in a formulation to modify the properties andcharacteristics of the polymers used in the coat(s) or core of theformulation for convenient processing during manufacture of the coat(s)and/or the core of the formulation. Once the coat(s) and/or core hasbeen manufactured, certain plasticizers can function to increase thehydrophilicity of the coat(s) and/or the core of the formulation in theenvironment of use. During manufacture of the coat(s) and/or core, theplasticizer can lower the melting temperature or glass transitiontemperature (softening point temperature) of the polymer or binder.

“Solid formulation” refers to a formulation that is neither liquid norgaseous. Solid formulations include tablets, powders, microparticles,capsules, matrix forms, suppositories, sachets, troches, patches andlozenges. Solid formulations in the form of capsules contain a solidcomposition within a capsule that can be made of gelatin or otherencapsulating material. Liquid formulations include liquid suspensionsand elixirs.

“Swelling enhancer” refers to an excipient that swells rapidly resultingin an increase in the size of the tablet. At lower concentrations, theseexcipients can be used as super disintegrants; however at higherconcentrations, e.g., at concentrations above about 5% w/w, theseexcipients function as swelling enhancers and increase the size of thematrix formulation.

“Therapeutically effective amount” refers to an amount of the drug that,when administered to a patient, will have the intended therapeuticeffect, e.g., alleviation, amelioration, palliation or elimination ofone or more manifestations of cancer or other hyperproliferative diseasein the patient. A therapeutic effect does not necessarily occur byadministration of one dose, and may occur only after administration of aseries of doses. Typically, cancer drugs are administered in a repeatingseries of doses, and in certain instances each series may be referred toas a “cycle” of therapy. Thus, a therapeutically effective amount may beadministered in one or more administrations.

“Treating” or “treatment of” a condition or patient refers to takingsteps to obtain beneficial or desired results, including clinicalresults. For purposes of this disclosure, beneficial or desired clinicalresults include, but are not limited to, in intended treatment purposeof ketamine such as pain, anesthesia, asthma, depression, or otherbeneficial results including reduction of side effects.

B. Oral Formulations

As demonstrated in the accompanying experimental examples, when ketaminewas administered with aspirin through two different route ofadministration (intraoral and oral) its efficacy was even better thanintravenously administered ketamine and was close to orally administeredMSIR (Morphine) (FIG. 1), and furthermore significantly better thanintravenously administered ketamine if corrected for expectedbioavailability of oral ketamine (oral ketamine is about 18-20%bioavailable, while IV ketamine is about 100% bioavailable). Meanwhile,the sedation and dissociation side effects were considerably reduced ascompared to intravenously administered ketamine (FIG. 2-3).

It is commonly known that oral ketamine has limited efficacy and, moreimportantly, ketamine from any route when administered at efficaciousdoses have side effects limiting outpatient use, and thus a narrowtherapeutic window outside of the monitored setting. Accordingly, oralketamine is not approved for outpatient use. It was further investigatedwhether a simple combination of oral aspirin and oral ketamine (oralaspirin/ketamine), or a dual route of ketamine (dual route ketamine)would have acceptable safety margin for outpatient use. Unexpectedly,the simple oral aspirin and ketamine administration resulted in a3.67-point pain reduction (FIG. 7), close to the dual routeaspirin/ketamine administration. The dual route ketamine, likewise,reached a 2.75-point reduction (FIG. 6) and only 25% SERSDA3+ adverseeven rate (FIG. 4). Such a safety margin is significantly improved ascompared to oral ketamine alone.

It is contemplated that such greatly improved efficacy and reduced sideeffects were at least in part attributed to the dual modes ofadministration of ketamine, one of which includes intraoraladministration for release in the mouth and absorption through themucosal membrane. The other portion of the ketamine was released in theGI track. The partial intraoral release and partial GI release ofketamine are contemplated to achieve a synergistic effect in increasingthe bioavailability and efficacy of ketamine. GI-absorbed ketamine has adifferent metabolic profile from intraorally absorbed ketamine whichdirectly enters into the blood stream. This is likely due to thefirst-pass metabolism of the liver for medication absorbed through theGI track.

When administered orally, ketamine undergoes first-pass metabolism,where it is biotransformed in the liver by CYP3A4 (major), CYP2B6(minor), and CYP2C9 (minor) isoenzymes into norketamine (throughN-demethylation) and ultimately dehydronorketamine. Intermediate in thebiotransformation of norketamine into dehydronorketamine is thehydroxylation of norketamine into hydroxynorketamine by CYP2B6 andCYP2A6. As the major metabolite of ketamine, norketamine is one-third toone-fifth as potent as an anesthetic, and plasma levels of thismetabolite are three times higher than ketamine following oraladministration.

Ketamine given directly into the blood stream results in a fast peak ofserum ketamine concentration, which immediately begins to drop. Theimmediate drop is due to the fast metabolism of ketamine into itsprimary metabolite, norketamine, resulting in high serum levels ofnorketamine.

Accordingly, the current data suggest that ketamine absorbed directlyinto the blood stream (such as oral mucosally absorbed) hits a peakserum concentration relatively quickly, within minutes. Ketamine givenconcurrently through the GI, on the other hand, has a serum peakconcentration about 15-20 minutes later. Therefore, when just focusingon the ketamine serum levels, a combination of direct-absorption andGI-absorption will “smooth out” the ketamine serum concentration overtime: the direct absorption getting serum levels high early, and the GIabsorption keeping serums level high later. This higher and wider serumlevel of ketamine result in a more pronounced effect.

It is further contemplated that the greatly improved efficacy andreduced side effects of ketamine were also attributed to the combinatoryuse of ketamine with aspirin. A combination of ketamine and aspirin iscontemplated to confer multimodal analgesia, with the contributions ofaspirin and ketamine to an opioid sparing effect. It is furthercontemplated that such effect of aspirin would be observed with othermodulators of glutamate ionotropic receptor NMDA type subunit 2A(GRIN2A), such as nicotine, propofol, melatonin, and gangliosides.Gangliosides are sialic acid-containing glycosphingolipids, among whichtetrasialoganglioside GQ1b is an example(alpha-N-acetylneuraminosyl-(2->8)-alpha-N-acetylneuraminosyl-(2->3)-beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminyl-(1->4)-[alpha-N-acetylneuraminosyl-(2->8)-alpha-N-acetylneuraminosyl-(2->3)]-beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1->1′)-N-(octadecanoyl)-sphing-4-enine;PubChem ID: 10887808).

Oral administration of ketamine results in decreased ketamine andincreased nor-ketamine concentrations in serum. Consequently, oralketamine's first-pass effect from hepatic metabolism of ketamine tonor-ketamine may help maintain analgesic potency while simultaneouslydecreasing side effects when compared to the IV form.

Aspirin is a prototype of non-steroidal anti-inflammatory drugs(NSAIDs), and member of the family of salicylates that have in commonsalicylic acid as the active agent. The pharmacological properties ofaspirin are similar to those of salicylates, but also to the biologicalactions attributed to salicylate itself, and it has other independenteffects due to its reactive acetate group. Both components, salicylateand acetate groups, are biologically active and act independently ofeach other at different sites. Aspirin is a safe and well-understoodnon-steroidal anti-inflammatory drug (NSAID). It has certain andclinically accepted analgesic properties. It is a non-selective andirreversible NSAID that inhibits an activity of both cyclooxygenase-1and 2 and blocks the synthesis of prostaglandins and thromboxanes.

An oral combination drug of aspirin (or another GRIN2A activator such asnicotine, propofol, melatonin and GQ1b) and ketamine (e.g., combinationof two administration route) would facilitate the shift from IV opioidsto a non-IV therapy for patients with acute MSK pain. This combinationhas a potential to provide effective analgesia with reduced sideeffects.

It is contemplated that the synergistic effects between intraoralketamine and oral ketamine, and between ketamine and aspirin, isapplicable to analogs and metabolites of ketamine and otherN-methyl-D-aspartate (NMDA) receptor antagonists, and applicable toother NSAIDs.

Example NMDA receptor antagonists include, without limitation, ketamine,dextromethorphan, memantine, and amantadine, as well as opioidsmethadone, dextropropoxyphene, and ketobemidone. Non-limiting examplesof ketamine metabolites include norketamine, hydroxynorketamine (HNK),dehydronorketamine (DHNK), and 6-hydroxyketamine (HK).

Accordingly, one embodiment of the present disclosure provides oralformulations of an NMDA receptor antagonist (e.g., ketamine or ametabolite or analog thereof) suitable/acceptable for outpatient use. Insome embodiments, provided is a pharmaceutical composition comprising afirst portion comprising a first amount of an NMDA receptor antagonist(e.g., ketamine or a metabolite or analog thereof), and a second portioncomprising a second amount of an NMDA receptor antagonist (e.g.,ketamine or a metabolite or analog thereof), wherein, upon oraladministration to a subject, the first portion disintegrates ordissolves intraorally providing rapid release of the NMDA receptorantagonist of the first portion, and the second portion is substantiallymore difficult than the first portion to disintegrate or dissolveintraorally but is ingestible and releasable in the gastrointestinaltrack of the subject.

In one aspect, the NMDA receptor antagonist (e.g., ketamine or ametabolite or analog thereof)of the first portion is at an amount lowerthan the regular dose of the NMDA receptor antagonist (e.g., 100-400mg), such as but not limited to, from about 10 mg to about 300 mg. Inone aspect, the amount of the NMDA receptor antagonist of the firstportion is at least about 10 mg, or least about 20 mg, 30 mg, 40 mg, 50mg, or 100 mg. In another aspect, the amount of the NMDA receptorantagonist of the first portion is no more than about 50 mg, 75 mg, 100mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg. Inone aspect, the NMDA receptor antagonist in the second portion is at anamount lower than the regular dose of the NMDA receptor antagonist(e.g., 100-400 mg), such as but not limited to, from about 10 mg toabout 300 mg. In one aspect, the amount of the NMDA receptor antagonistof the first portion is at least about 10 mg, or least about 20 mg, 30mg, 40 mg, 50 mg, or 100 mg. In another aspect, the amount of the NMDAreceptor antagonist of the first portion is no more than about 50 mg, 75mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or300 mg.

In one aspect, the NMDA receptor antagonist (e.g., ketamine or ametabolite or analog thereof)of the first portion is at least about 10%,or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of atherapeutically effective amount. In one aspect, the NMDA receptorantagonist of the first portion is at most about 10%, or 20%, or 30%, or40%, of 50%, or 60%, or 70%, or 80%, or 90% of a therapeuticallyeffective amount. In one aspect, the NMDA receptor antagonist of thesecond portion is at least about 10%, or 20%, or 30%, or 40%, of 50%, or60%, or 70%, or 80%, or 90% of a therapeutically effective amount. Inone aspect, the NMDA receptor antagonist of the second portion is atmost about 10%, or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%,or 90% of a therapeutically effective amount.

In one aspect, the first portion of the NMDA receptor antagonist (e.g.,ketamine or a metabolite or analog thereof)constitutes at least about10% of the total NMDA receptor antagonist in the composition.Alternatively, the first portion of the NMDA receptor antagonistconstitutes at least about 20%, or 30%, or 40%, or 50%, or 60%, or 70%,or 80%, or 90% of the total NMDA receptor antagonist. In some aspects,however, the first portion of the NMDA receptor antagonist can be lessthan about 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%of the total NMDA receptor antagonist. In a particular aspect, the firstportion constitutes from about 40% to about 60%, or alternatively fromabout 45% to about 55% of the total NMDA receptor antagonist.

In one aspect, the total amount of the NMDA receptor antagonist (e.g.,ketamine or a metabolite or analog thereof)in the composition is lessthan about 50 mg, or 60 mg, or 70 mg, or 80 mg, or 90 mg, or 100 mg, or120 mg, or 140 mg, or 150 mg, or 160 mg, or 165 mg, or 170 mg, or 180mg, or 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg,270 mg, 280 mg, 290 mg, or 300 mg. In another aspect, the total amountof the NMDA receptor antagonist in the composition is greater than about10 mg, 20 mg, or 30 mg, or 40 g, or 50 mg, or 60 mg, or 70 mg, or 80 mg,or 90 mg, or 100 mg, or 110 mg, or 120 mg, or 130 mg, or 140 mg, or 150mg.

It is further contemplated that the addition of aspirin (or moregenerally an NSAID) can further enhance the bioavailability and/orefficacy of the NMDA receptor antagonist (e.g., ketamine or a metaboliteor analog thereof). In one embodiment, aspirin (or NSAID) is added tothe first portion of the NMDA receptor antagonist which disintegrates ordissolves intraorally providing rapid release of the NMDA receptorantagonist of the first portion. In some embodiments, the aspirin in thefirst portion is at least about 40 mg. In some embodiments, the aspirinin the first portion is at least about 80 mg, 160 mg, 240 mg or 320 mg.

In one embodiment, aspirin is added to the second portion of the NMDAreceptor antagonist which is substantially more difficult than the firstportion to disintegrate or dissolve intraorally but is ingestible andreleasable in the gastrointestinal track of the subject. In someembodiments, the aspirin in the second portion is at least about 40 mg.In some embodiments, the aspirin in the second portion is at least about80 mg, 160 mg, 240 mg or 320 mg.

Another aspect of the invention provides a process of preparing thedisclosed compositions. In some embodiments, the process comprisesforming a first portion and a second portion and compressing the firstand second portions to form a bilayer or two-halves compressed solidoral dosage form. Preparation of each portion is further describedbelow.

1. First Portion of NMDA Receptor Antagonist for Intraoral Release

Methods of preparing a composition suitable for intraoral release areknown in the art. In one aspect, the first portion further includes afilm-coating agent, an excipient, a binder, a lubricant, or aplasticizer.

In one aspect, the first portion disintegrates or dissolves intraorallywithin about 10 minutes. In other aspects, the first portiondisintegrates or dissolves intraorally within about 9 minutes, or about8, or about 7, or about 6, or about 5, or about 4, or about 3 or about 2minutes, or alternatively about 60 seconds, or about 50, or about 40, orabout 30, or about 20, or about 10, or about 5 seconds.

In some aspects, the first portion is chewable. In some aspects, thefirst portion is in the form of molded triturate.

In one aspect, the first portion further includes an agent that promotesthe oral or buccal absorption of the NMDA receptor antagonist.Non-limiting examples of such agents include bile acid salts, sodiumlauryl sulfate, lysalbinic acid, salicylic acid, 5-methoxy salicylicacid, 3,4-dihydroxy phenyl acetic acid (DOPAC) and homovanillic acid andtheir sodium salts thereof. Other hydroxyaryl acids, such as1-hydroxy-2-naphthoic acid, naphthoresorcyclic acid, ferulic acid,caffeic acid, resorcylic acid and gentisic acid, have similar effects.

The amount of hydroxyaryl or hydroxyaralkyl acid or salt, amide or esterderivatives thereof forms may vary over a wide range; in general, theidentity and the amount of the hydroxyaryl or hydroxyaralkyl acids orsalt, amide or ester thereof is used in connection with the drug inorder to be effective in enhancing the absorption rate of the drug intothe bloodstream.

In another aspect, the first portion further includes a disintegrant.Non-limiting examples of disntegrants include crospovidone, crystallinecellulose, hydroxypropylcellulose with a low degree of substitution,croscarmellose sodium, carmellose calcium, carboxystarch sodium,carboxymethyl starch sodium, potato starch, wheat starch, corn starch,rice starch, partly pregelatinized starch, and hydroxypropyl starch. Oneor two or more of these can be used together. Coating with adisintegrant also contributes to improvement of compression moldability.

2. Second Portion of NMDA Receptor Antagonist, and Optionally ThirdPortion of Aspirin, for GI Release

The second and third portions of the composition can be prepared withmethods known in the art for a typical oral dosage form suitable for GIabsorption. Like the first portion, the second portion can also includea film-coating agent, an excipient, a binder, a lubricant, or aplasticizer.

Compared to the first portion, the second is substantially moredifficult to disintegrate or dissolve intraorally. This can be achievedchemically or physically. For instance, the second portion can bephysically harder. In one aspect, the second portion is compressed. Inanother aspect, the second portion has a hardness that is at least about10 kilopascal (kp), or alternatively about 11, or 12, or 13, or 14, or15, or 20, or 25 or 30 or 40 or 50 kp.

Hardness can be assessed by means commonly used in the art, for example,using commercially available hardness testers that are routinely usedfor assessing the hardness of pharmaceutical dosage forms.

In some aspects, the second portion further comprises a pharmaceuticallyacceptable flavoring agent not present in the first portion. Theflavoring agent provides a flavor that alerts the patients that thisportion should not be chewed and needs to be swallowed so as to increasepatient compliance.

In one aspect, the NMDA receptor antagonist in the second portionconstitutes at least about 10% of the total NMDA receptor antagonist.Alternatively, the NMDA receptor antagonist in the second portionconstitutes at least about 20%, or 30%, or 40%, or 50%, or 60%, or 70%,or 80%, or 90% of the total NMDA receptor antagonist. In some aspects,however, the NMDA receptor antagonist in the second portion can be lessthan about 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%of the total NMDA receptor antagonist. In a particular aspect, the NMDAreceptor antagonist in second portion constitutes from about 40% toabout 60%, or alternatively from about 45% to about 55% of the totalNMDA receptor antagonist. In one aspect, the ratio of the NMDA receptorantagonist between the first portion and the second portion is about1:1. Alternatively, the ratio is at least about 1:4, or 1:3, or 1:2 or1:1.5, or is no more than about 4:1, 3:1, 2:1 or 1.5:1.

The pharmaceutical composition of the present disclosure can be in theform of a tablet or capsule. When in the form of a tablet, the secondportion, in one aspect, is enclosed within the first portion oralternatively partially exposed.

When the composition is in the form of a tablet, the tablet can includean outer portion and an inter portion, with the outer portion containingthe first portion and the inner portion containing the second portionand optionally the third portion.

In one aspect, the outer portion is formulated to dissolve in the oralcavity of a subject and to release the NMDA receptor antagonist in thefirst portion across the oral mucosa of the subject. In one aspect, theinner portion is harder than the outer portion and is formulated fordissolving in stomach, intestines, or further distal in thegastrointestinal tract of the subject.

In one aspect, the inner portion comprises a texture on the surface thatis recognizable by the tongue of a subject. In another aspect, the outerportion comprises a water soluble sugar or sugar substitute. In anotheraspect, the outer portion is surrounded by a thin shell to allowencapsulation of liquid, powder or gel in the outer portion.

In one aspect, the outer potion is flavored or sweetened. In one aspect,the tablet further comprises an intermediate layer between the outer andinner portions. In one aspect, the intermediate layer comprises entericcoating. In one aspect, the inner portion is formulated to absorb abiting shock and not break a tooth. In another aspect, the tabletcomprises a layer of ketamine which breaks down in the mouth, but thislayer has particles within it that don't completely break down in themouth and stay full particles, such that there is partial intraoralrelease and, when the particles as swallowed, partial gastrointestinalrelease.

The pharmaceutical composition of the above embodiments can furtherinclude a third portion that comprises an effective amount of aspirin.In one aspect, the third portion is in the form of controlled release.In another aspect, the third portion further comprises enteric coating.In yet another aspect, the third portion is enclosed in the firstportion or the second portion.

3. Combination of NMDA Receptor Antagonist and GRIN2A Modulator

Another discovery of the present disclosure is that certain desiredeffects of an NMDA receptor antagonist (e.g., ketamine or a metaboliteor analog thereof), such as pain reduction, suppression of depression,reduction of fatigue, can be further enhanced by co-administration withaspirin. The co-administration of aspirin, or another GRIN2A modulator,is also associated with a reduction of the undesired effects of the NMDAreceptor antagonist, including its sedation effect and addictionpotential.

In accordance with one embodiment of the disclosure, provided is apharmaceutical composition comprising an NMDA receptor antagonist (e.g.,ketamine or a metabolite or analog thereof)and a glutamate ionotropicreceptor NMDA type subunit 2A (GRIN2A) modulator. In some embodiments,the GRIN2A modulator is an activator. Non-limiting examples includeaspirin, nicotine, propofol, melatonin and GQ1b.

In some embodiments, the NMDA receptor antagonist in the composition isprovided as two portions, with the first portion comprising a firstamount of the NMDA receptor antagonist, and a second portion comprisinga second amount of the NMDA receptor antagonist, wherein, upon oraladministration to a subject, the first portion disintegrates ordissolves intraorally providing rapid release of the NMDA receptorantagonist of the first portion, and the second portion is substantiallymore difficult than the first portion to disintegrate or dissolveintraorally but is ingestible and releasable in the gastrointestinaltrack of the subject.

In some embodiments, the GRIN2A modulator is formulated together withthe first portion of the NMDA receptor antagonist. In some embodiments,the GRIN2A modulator is formulated together with the second portion ofthe NMDA receptor antagonist. In some embodiments, the GRIN2A modulatoris formulated together with each of the first portion and the secondportion of the NMDA receptor antagonist.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising an NMDA receptor antagonist and aspirin. Eitheror both of the NMDA receptor antagonist and aspirin can be formulatedfor both intraoral and oral administration, as described throughout.

In some embodiments, the NMDA receptor antagonist (e.g., ketamine or ametabolite or analog thereof)is at an amount lower than the regular doseof the NMDA receptor antagonist (e.g., 100-400 mg), such as but notlimited to, from about 20 mg to about 300 mg. In one aspect, the amountof the NMDA receptor antagonist of the first portion is at least about20 mg, or least about 30 mg, 40 mg, 50 mg, or 100 mg. In another aspect,the amount of the NMDA receptor antagonist of the first portion is nomore than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg or 300 mg.

In some embodiments, the composition includes two portions of aspirin, afirst portion containing a first amount of the aspirin, and a secondportion containing a second amount of the aspirin. Upon oraladministration to a subject, the first portion disintegrates ordissolves intraorally providing rapid release of the aspirin of thefirst portion, and the second portion is substantially more difficultthan the first portion to disintegrate or dissolve intraorally but isingestible and releasable in the gastrointestinal track of the subject.

4. Additional Additives to the Compositions

In yet another aspect, either or both of the first portion and secondportion further comprises excipients, lubricants, pH adjusters,taste-masking agents, sweeteners, acidifiers, refrigerants, foamingagents, preservatives, fluidizers, antioxidants, colorants, stabilizers,surfactants, buffering agents, flavors, binders or drug solubilizers. Aperson skilled in the art may immediately list specific examples ofthese additives.

Any excipient used for pharmaceutical preparations can be used withoutlimitation, but examples of excipients used in the tablet of the presentinvention can include sugars such as erythritol, mannitol, xylitol,sorbitol, lactitol, paratinit, paratinose, maltitol, maltose, trehalose,lactose, sucrose, glucose, olygosaccharides, fructose and maltose andthe like. One or two or more kinds of these excipients can be used.

Various embodiments of the composition may include pharmaceuticallyacceptable binders (adhesives). Binders are agents that impart cohesiveproperties to powdered materials through particle-particle bonding.Examples of suitable binders include celluloses and crosslinkedpolyvinyl pyrrolidone, matrix binders (dry starch, dry sugars), filmbinders (polyvinyl pyrrolidone (PVP), starch paste, celluloses,bentonite, sucrose), and chemical binders (polymeric cellulosederivatives, such as carboxy methyl cellulose, hydroxypropylcellulose(HPC) and hydroxypropylmethylcellulose (HPMC); sugar syrups; corn syrup;water soluble polysaccharides such as acacia, tragacanth, guar andalginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; andnon-cellulosic binders, such as polyvinyl pyrrolidone, polyethyleneglycol (PEG), vinyl pyrrolidone copolymers, pregelatinized starch,sorbitol, glucose, microcrystalline cellulose, such as FMC BioPolymer'sAvicel® PH101 and Avicel® PH102, and silicified microcrystallinecellulose, such as Penwest Pharmaceutical's ProSolv SMCC™). In specificembodiments, a binder is selected from the group consisting of cornstarch, potato starch, polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and hydroxylpropyl cellulose. A binder may be included in anyportion of the dosage form, such as the intragranular portion and/orextragranular portion of either or both of the first and second layers.

In some embodiments, the composition further comprises apharmaceutically acceptable diluent or filler. Pharmaceuticallyacceptable diluents include, but are not limited to, lactose (such aslactose monohydrate, lactose anhydrous, and DMV International'sPharmatose® DCL21 crystalline alpha monohydrate milled lactose),mannitol, talc, magnesium stearate, sodium chloride, potassium chloride,citric acid, spray-dried lactose, starch, hydrolyzed starches, directlycompressible starch, microcrystalline cellulose (such as Avicel® PH101and Avicel® PH102), cellulosics, sorbitol, sucrose, glucose,sucrose-based materials, saccharides, calcium sulfate, dibasic calciumphosphate (such as Emcompress®) and dextrose, and/or mixtures of any ofthe foregoing. In specific embodiments, a diluent is selected from thegroup consisting of microcrystalline cellulose, lactose, mannitol,dicalcium phosphate, dextrose, compressible sugar, and spray-driedlactose with microcrystalline cellulose. A diluent may be may beincluded in any portion of the dosage form, such as the intragranularportion and/or extragranular portion of either or both of the first andsecond layers.

In some embodiments, the composition comprises magnesium stearate. Inspecific embodiments, the magnesium stearate is present in a range ofabout 0.5% to 2% w/w, based on the total weight of the layer.

In some embodiments, the diluent is microcrystalline cellulose ormicrolac (spray-dried lactose with microcrystalline cellulose). Inspecific embodiments, the microcrystalline cellulose or microlac ispresent in a range of about 20% to 60% w/w, based on the total weight ofthe layer.

Various embodiments of the invention may include pharmaceuticallyacceptable anti-adherents (anti-sticking agents, glidants, flowpromoters, lubricants) such as talc, colloidal silicon dioxide, such asAerosil® 200, magnesium stearate, fumed silica (Carbosil, Aerosil),micronized silica (Syloid No. FP 244, Grace U.S.A.), polyethyleneglycols, surfactants, waxes, stearic acid, stearic acid salts, stearicacid derivatives, calcium stearate, silica gel, starch, hydrogenatedvegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000, andmagnesium lauryl sulfate. In specific embodiments, an anti-adherents isselected from glidants and lubricants. Suitable glidants include, butare not limited to, colloidal silicon dioxide (Aerosil®), magnesiumtrisilicate, talc, and tribasic calcium phosphate. Suitable lubricantsinclude, but are not limited to magnesium, aluminum, calcium, zincstearate, and talc. An anti-adherent may be included in any portion ofthe dosage form, such as the intragranular portion and/or extragranularportion of either or both of the first and second layers. In specificembodiments, an anti-adherent is included in the extragranular portionof the first layer and/or the extragranular portion of the second layer.

In some embodiments, the glidant is talc. In specific embodiments, talcis present in a range of about 1% to 7% w/w, based on the total weightof each layer.

C. Therapeutic Methods

Therapeutic methods are also provided. In one aspect, provided is amethod of administering ketamine to a subject with improved efficacy orbioavailability, comprising administering to the subject (a) a firstcomposition comprising a first amount of ketamine and (b) a secondcomposition comprising a second amount of ketamine, wherein the firstcomposition disintegrates or dissolves intraorally providing rapidrelease of the ketamine of the first portion, and the second compositionis ingested and released in the gastrointestinal track of the subject.

In one aspect, the ketamine of the first composition is at an amountlower than the regular dose of ketamine (e.g., 10-400 mg), such as butnot limited to, from about 10 mg to about 300 mg. In one aspect, theamount of ketamine of the first composition is at least about 10 mg, orleast about 20 mg, 30 mg, 40 mg, 50 mg, or 100 mg. In another aspect,the amount of ketamine of the first composition is no more than about 50mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275mg or 300 mg. In one aspect, the ketamine in the second composition isat an amount lower than the regular dose of ketamine (e.g., 100-400 mg),such as but not limited to, from about 10 mg to about 300 mg. In oneaspect, the amount of ketamine of the first composition is at leastabout 10 mg, or least about 20 mg, 30 mg, 40 mg, 50 mg, or 100 mg. Inanother aspect, the amount of ketamine of the first composition is nomore than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg or 300 mg.

In one aspect, the ketamine of the first composition is at least about10%, or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of atherapeutically effective amount. In one aspect, the ketamine of thefirst composition is at most about 10%, or 20%, or 30%, or 40%, of 50%,or 60%, or 70%, or 80%, or 90% of a therapeutically effective amount. Inone aspect, the ketamine of the second composition is at least about10%, or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of atherapeutically effective amount. In one aspect, the ketamine of thesecond composition is at most about 10%, or 20%, or 30%, or 40%, of 50%,or 60%, or 70%, or 80%, or 90% of a therapeutically effective amount.

In one aspect, the first composition of ketamine constitutes at leastabout 10% of the total ketamine administered. Alternatively, the firstcomposition of ketamine constitutes at least about 20%, or 30%, or 40%,or 50%, or 60%, or 70%, or 80%, or 90% of the total ketamine. In someaspects, however, the first composition of ketamine can be less thanabout 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90% of thetotal ketamine. In a particular aspect, the first compositionconstitutes from about 40% to about 60%, or alternatively from about 45%to about 55% of the total ketamine.

In one aspect, the total amount of ketamine administered is less thanabout 50 mg, or 60 mg, or 70 mg, or 80 mg, or 90 mg, or 100 mg, or 120mg, or 140 mg, or 150 mg, or 160 mg, or 165 mg, or 170 mg, or 180 mg, or190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg,280 mg, 290 mg, or 300 mg. In another aspect, the total amount ofketamine administered is greater than about 10 mg, 20 mg, or 30 mg, or40 g, or 50 mg, or 60 mg, or 70 mg, or 80 mg, or 90 mg, or 100 mg, or110 mg, or 120 mg, or 130 mg, or 140 mg, or 150 mg.

Also provided, in one embodiment, is a method for treating acute pain ina patient, comprising orally administering an effective amount ofketamine to the patient.

The effective amount may be at least 0.1 mg/kg, or at least 0.2 mg/kg,0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95 or 1 mg/kg. In some embodiments, the effective amount is notgreater than 2 mg/kg, or not greater than 1.9 mg/kg, 1.85, 1.8, 1.75,1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1,1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, or 0.5 mg/kg.In some embodiments, the effective amount is from 0.3 mg/kg to 0.8mg/kg, preferably from 0.4 mg/kg to 0.6 mg/kg, and more preferably 0.5mg/kg.

Also provided, in one embodiment, is a method for treating acute onchronic headache in a patient, comprising orally administering aneffective amount of ketamine to the patient.

The effective amount may be at least 0.1 mg/kg, or at least 0.2 mg/kg,0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95 or 1 mg/kg. In some embodiments, the effective amount is notgreater than 2 mg/kg, or not greater than 1.9 mg/kg, 1.85, 1.8, 1.75,1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1,1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, or 0.5 mg/kg.In some embodiments, the effective amount is from 0.5 mg/kg to 1.5mg/kg, preferably from 0.7 mg/kg to 1 mg/kg, and more preferably 0.85mg/kg.

Also provided, in one embodiment, is a method for treating depression ina patient, comprising orally administering an effective amount ofketamine to the patient.

The effective amount may be at least 0.1 mg/kg, or at least 0.2 mg/kg,0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95 or 1 mg/kg. In some embodiments, the effective amount is notgreater than 2 mg/kg, or not greater than 1.9 mg/kg, 1.85, 1.8, 1.75,1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1,1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, or 0.5 mg/kg.In some embodiments, the effective amount is from 0.75 mg/kg to 1.75mg/kg, preferably from 1 mg/kg to 1.5 mg/kg, and more preferably 1.2mg/kg.

Also provided, in one embodiment, is a method for treating cannabinoidhyperemesis syndrome exacerbations in a patient, comprising orallyadministering an effective amount of ketamine to the patient.

The effective amount may be at least 0.1 mg/kg, or at least 0.2 mg/kg,0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95 or 1 mg/kg. In some embodiments, the effective amount is notgreater than 2 mg/kg, or not greater than 1.9 mg/kg, 1.85, 1.8, 1.75,1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1,1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, or 0.5 mg/kg.In some embodiments, the effective amount is from 0.2 mg/kg to 1 mg/kg,preferably from 0.2 mg/kg to 0.6 mg/kg, and more preferably 0.4 mg/kg.It is further contemplated that the addition of an GRIN2A modulator,e.g., aspirin, can further enhance the bioavailability and/or efficacyof the ketamine. In accordance with one embodiment of the disclosure,provided is a method of administering ketamine to a subject withimproved efficacy or bioavailability, or reduced side effects,comprising administering to the subject ketamine and a glutamateionotropic receptor NMDA type subunit 2A (GRIN2A) modulator. In someembodiments, the GRIN2A modulator is an activator. Non-limiting examplesinclude aspirin, nicotine, propofol, melatonin and GQ1b.

In some embodiments, the ketamine is provided as two portions or twocompositions, with the first portion/composition comprising a firstamount of ketamine, and a second portion/composition comprising a secondamount of ketamine, wherein, upon oral administration to a subject, thefirst portion/composition disintegrates or dissolves intraorallyproviding rapid release of the ketamine of the first portion, and thesecond portion/composition is substantially more difficult than thefirst portion to disintegrate or dissolve intraorally but is ingestibleand releasable in the gastrointestinal track of the subject.

In some embodiments, the GRIN2A modulator is absorbed intraorally. Insome embodiments, the GRIN2A modulator is absorbed in the GI track. Insome embodiments, the GRIN2A modulator is partially absorbed intraorallyand partially absorbed in the GI track.

In some embodiments, the GRIN2A modular is aspirin. In one embodiment,aspirin is administered in a manner that disintegrates or dissolvesintraorally providing rapid release of the ketamine of the firstcomposition. In some embodiments, the aspirin so administered is atleast about 40 mg. In some embodiments, the aspirin is at least about 80mg, 160 mg, 240 mg or 320 mg.

In one embodiment, aspirin is administered such that it is substantiallymore difficult than the first composition to disintegrate or dissolveintraorally but is ingestible and releasable in the gastrointestinaltrack of the subject. In some embodiments, the aspirin so administeredis at least about 40 mg. In some embodiments, the aspirin soadministered is at least about 80 mg, 160 mg, 240 mg or 320 mg.

It is also contemplated that a single composition of ketamine can alsobe used to achieve the desired effect, when a portion of the ketamine isdissolved intraorally and the remaining is released in the GI track.Such a composition of ketamine can be combined with aspirin, asdisclosed above.

Thus, also provided is a method of administering ketamine to a subjectin need of treating a disease or condition, comprising administering tothe subject a therapeutically effective amount of ketamine, wherein aportion of the ketamine disintegrates or dissolves intraorally within 10minutes permitting rapid release of the ketamine in the portion, and theremaining ketamine is ingested and released in the gastrointestinaltrack of the subject.

The disease or condition, without limitation, can be pain, asthma, ordepression. In some embodiments, the subject is need of anesthesia.

In some aspects, the first composition or portion of the ketaminedisintegrates or dissolves intraorally within about 9 minutes, or about8, or about 7, or about 6, or about 5, or about 4, or about 3 or about 2minutes, or alternatively about 60 seconds, or about 50, or about 40, orabout 30, or about 20, or about 10, or about 5 seconds. In anyembodiment of the above methods, the method further comprisesadministering to the subject an effective amount of aspirin.

Also provided, in one embodiment, is a method of administering ketamineto a subject, comprising administering to the subject ketamine andaspirin.

In some embodiments, the aspirin is administered as (a) a firstcomposition comprising a first amount of aspirin and (b) a secondcomposition comprising a second amount of aspirin, wherein the firstcomposition disintegrates or dissolves intraorally providing rapidrelease of the aspirin of the first portion, and the second compositionis ingested and released in the gastrointestinal track of the subject.In some embodiments, the ketamine is administered as (a) a firstcomposition comprising a first amount of ketamine and (b) a secondcomposition comprising a second amount of ketamine, wherein the firstcomposition disintegrates or dissolves intraorally providing rapidrelease of the ketamine of the first portion, and the second compositionis ingested and released in the gastrointestinal track of the subject.

In some embodiments, the ketamine is at an amount lower than the regulardose of ketamine (e.g., 10-400 mg), such as but not limited to, fromabout 20 mg to about 300 mg. In one aspect, the amount of ketamine ofthe first portion is at least about 20 mg, or least about 30 mg, 40 mg,50 mg, or 100 mg. In another aspect, the amount of ketamine of the firstportion is no more than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg.

The administration of ketamine can be useful for treating certaindiseases or conditions, such as pain, asthma, or depression. In someembodiments, the subject is need of anesthesia.

EXAMPLE 1 Dual-Route Ketamine and Aspirin in Musculoskeletal PainReduction

This example evaluates analgesic efficacy of dual-route ketamine (liquidintraoral ketamine+oral ketamine) taken simultaneously with dual-routeaspirin (intraoral aspirin+oral aspirin) for pain management of adultemergency department (ED) patients presenting to the ED with acutemusculoskeletal pain.

It is contemplated that the treatment will result in analgesia with achange in pain score at least of 1.3 points on numeric rating pain scale(NRS). The primary outcome of this test is the reduction inparticipant's pain scores at 60 minutes post medication administration.

Subjects: Patients 18 years of age and older presenting to the ED withacute musculoskeletal painful conditions (traumatic and non-traumatic)with an initial pain score of 5 or more on a standard 11-point (0 to 10)numeric rating scale and requiring oral analgesia as determined by thetreating attending physician. Study investigators and researchassistants will perform patients' screening and enrollment. All patientswill be enrolled at various times of the day when study investigatorswill be available for patient enrollment and an ED pharmacist will beavailable for medication preparation.

Eligibility Criteria: Patients 18 years of age and older presenting tothe ED with acute musculoskeletal painful conditions (traumatic andnon-traumatic) with an initial pain score of 5 on a standard 11-point (0to 10) numeric rating scale. Patients will be awake, alert, oriented toperson, place, and time, and will be able to demonstrate understandingof the informed consent process and content. Patients also will have todemonstrate ability to verbalize the nature of any adverse effects theymight experience as well as to express their pain severity by using theNRS.

Exclusion Criteria: Patients with: altered mental status, allergy toaspirin and ketamine, pregnant patients, unstable vital signs (systolicblood pressure <90 or >180 mm Hg, pulse rate <50 or >150 beats/min, andrespiration rate <10 or >30 breaths/min), inability to provide consent,consumption of Aspirin or NSAID' s within 6 hours of arrival to the ED,active PUD, history of GI Hemorrhage, history of renal and hepaticinsufficiency, past medical history of alcohol or drug abuse, orschizophrenia.

Design: This is a prospective observational pilot trail evaluatinganalgesic efficacy and safety of dual-route ketamine in adult patientspresenting to the ED of Maimonides Medical Center with acutemusculoskeletal painful conditions. Upon meeting the eligibilitycriteria, patients will be offered to participate in the study.

Data Collection Procedures: Each patient will be approached by a studyinvestigator for acquisition of written informed consent and HealthInsurance Portability and Accountability Act authorization after beingevaluated by the treating emergency physician and determined to meetstudy eligibility criteria. When English is not the participant'sprimary language, a language-appropriate consent form will be used andnon-investigator, hospital-employed, trained interpreters or licensedtelephone interpreter will assist in acquisition of informed consent.Baseline pain score will be determined with an 11-point numeric ratingscale (0 to 10), described to the patient as “no pain” being 0 and “theworst pain imaginable” being 10. A study investigator will record thepatient's body weight and baseline vital signs.

The on-duty ED pharmacist will prepare an oral dose of ketamine by usinga formulary for parenteral use. The oral dosing regimen of ketamine is0.5 mg/kg that will be placed in the syringe or a medication cup andsweetener (Ora-sweet®) will be added to offset unpleasant taste of theketamine. The total dose for aspirin is 325 mg as specified by thesponsor. The research associate will deliver both medications(dual-route aspirin and dual-route ketamine) to the patients' nurse.Study investigators will record pain scores and adverse effects at 15,30, 60, 90, and 120 minutes. If patients reported a pain numeric ratingscale score of 5 or greater and requested additional pain relief, anoral immediate release morphine tablet of 7.5 mg will be given.

All data will be recorded on data collection sheets, including patients'sex, demographics, medical history, and vital signs, and entered intoSPSS (version 24.0; IBM Corp) by the research manager. The statistician,who will work independently of any data collection, will conductstatistical analyses.

Patients will be closely monitored for adverse effects during the entirestudy period (up to 120 minutes) by study investigators. Common adverseeffects that are associated with oral ketamine are felling of unreality,dizziness, nausea, vomiting, and sedation. Common adverse effects areassociated with dual-route aspirin are nausea, dyspepsia, epigastricdiscomfort.

Data Analysis: Data analyses will include frequency distributions andindependent-sample t-test to assess differences in pain scores at thevarious intervals. Mixed-model linear regression will be used to comparechanges in pain on numeric rating scale across time points.

For categorical outcomes (e.g., complete resolution of pain), X² orFisher's exact test will be used to compare outcomes at 60 minutes.Based on the validation of a verbally administered rating scale of acutepain in the ED and the comparison of verbal and visual pain scales, thisexample will use a primary outcome consisting of a minimal clinicallymeaningful difference of 1.3 between three groups at the 60-minute painassessment.

Sample Size: Assuming a minimal clinically meaningful difference of 1.3in change of pain score from the baseline until 60 minutes, given astandard deviation of 3.0, with a one-side 97.5% confidence interval,this example will need 21 subjects for this pilot trial. This examplewould enroll 25 patients to account for any loss to follow-up.

Expected Outcomes: The primary outcome will include a reduction of painscores on numeric rating pain scale (NRS) at 60 minutes mark form thebaseline. The secondary outcomes will include a need for rescueanalgesia and rates of adverse up to 90 minutes. With respect to uniqueadverse effects of SDK, this example will use Side Effect Rating Scalefor Dissociative Anesthetics (SERSDA) and Richmond Agitation SedationScale (RASS). SERSDA Scale includes fatigue, dizziness, nausea,headache, feeling of unreality, changes in hearing, mood change, generaldiscomfort, and hallucinations with severity of each graded by patientson a five-point scale, with “0” representing the absence of any adverseeffects and “4” representing a severely bothersome side effect. RASSevaluates the severity of agitation and/or sedation in accordance to thenine-point scale with scores ranging from “−4” (deeply sedated) to “0”(alert and calm) to “+4” (combative).

Adverse Events: Dizziness, nausea, vomiting, agitation and or sedation,weakness or fatigue, feelings of unreality, epigastric pain, dyspepsia.

SAE Reporting: Any serious adverse event, requiring intervention, willbe reported to the IRB within 24 hours of discovery by the researchstaff. Less serious adverse events will be reported within a week ofdiscovery. There are known expected outcomes and side effects to theprocedures and medications being received and these are the samerisks/side effects as the standard of care—these will be reported ifthey are serious and require intervention.

Timetable: The entire study (from commencement until recruitment of thelast patient) will last 12 months. The research team will monitor andrecord each patient's pain scores and adverse events. The research team,pharmacist, and research manager will be immediately aware and/ornotified if a serious adverse event occurs. ED team of physicians andnurses will treat the patient appropriately, and subsequently theadverse effect report will be filed to the IRB.

EXAMPLE 2 Comparison of Ketamine/Aspirin with Ketamine Alone

This example compares dual-route ketamine (oral+intraoral) to oralketamine alone plus oral aspirin alone in adult patients presenting tothe ED with acute musculoskeletal pain, in a randomized, double-blind,clinical trial.

Oral formulations of ketamine are not commercially available. Theparenteral formulation is given as an oral solution by using aninjectable vial. The oral bioavailability of ketamine, defined as areaunder plasma concentration time curve (AUC), after a single oral dose of0.5 mg/kg is about one fifth of the availability after an intravenousinjection. In a ketamine-naive patient, oral administration of ketaminecan start with a single dose of 0.5 mg/kg ketamine racemic mixture or0.25 mg/kg S-ketamine to evaluate the effect on pain relief and theduration of effect.

Doses can be increased in steps of 0.5 or 0.25 mg/kg according to theefficacy and adverse effects, respectively. The average dosing frequencyof 3-4 times daily found in the clinical studies corresponds well withthe elimination half-lives of ketamine (2-3 h) and nor-ketamine (4 h).The conversion from parenteral to oral administration in an equipotentdose is complex and is not solely based on a reduced bioavailability.The median conversion rate from subcutaneous to oral ketamine used inthe case reports was 1:1.

The primary outcome of this trial is the comparative reduction inparticipant's pain scores at 60 minutes post-medication administration.

Example Arms and Interventions

Arms Assigned Intervention Ketamine + Aspirin 0.5 mg/kg of ketamine(oral) + 324 mg of aspirin (oral) Ketamine alone 0.5 mg/kg of ketamine(dual-route) (oral + intraoral)

Subjects: Patients 18 years of age and older presenting to the ED withacute musculoskeletal painful conditions (traumatic and non-traumatic)with an initial pain score of 5 or more on a standard 11-point (0 to 10)numeric rating scale and requiring oral analgesia as determined by thetreating attending physician. Patients' screening and enrollment will beperformed by study investigators and research assistants. All patientswill be enrolled at various times of the day when study investigatorswill be available for patient enrollment and an ED pharmacist will beavailable for medication preparation.

Eligibility Criteria: Patients 18 years of age and older presenting tothe ED with acute musculoskeletal painful conditions (traumatic andnon-traumatic) with an initial pain score of 5 on a standard 11-point (0to 10) numeric rating scale. Patients will have to be awake, alert, andoriented to person, place, and time, and will be able to demonstrateunderstanding of the informed consent process and content. Patients alsowill have to demonstrate ability to verbalize the nature of any adverseeffects they might experience as well as to express their pain severityby using the NRS.

Exclusion Criteria: Patients with altered mental status, allergy toaspirin and ketamine, pregnant patients, unstable vital signs (systolicblood pressure <90 or>180 mm Hg, pulse rate <50 or >150 beats/min, andrespiration rate <10 or >30 breaths/min), inability to provide consent,consumption of Aspirin or NSAID' s within 6 hours of arrival to the ED,active PUD, history of GI Hemorrhage, history of renal and hepaticinsufficiency, past medical history of alcohol or drug abuse, orschizophrenia.

Design: This is a prospective, randomized, double-blind trial comparinganalgesic efficacy and safety of the treatments in patients presentingto the ED of Maimonides Medical Center with acute musculoskeletal pain.Upon meeting the eligibility criteria, patients will be randomized intoone of the two study arms: 325 mg dual-route aspirin+1 mg/kg oralketamine, and oral ketamine alone at 1 mg/kg.

Data Collection Procedures: Each patient will be approached by a studyinvestigator for acquisition of written informed consent and HealthInsurance Portability and Accountability Act authorization after beingevaluated by the treating emergency physician and determined to meetstudy eligibility criteria. When English is not the participant'sprimary language, a language-appropriate consent form will be used andnon-investigator, hospital-employed, trained interpreters or licensedtelephone interpreter will assist in acquisition of informed consent.Baseline pain score will be determined with an 11-point numeric ratingscale (0 to 10), described to the patient as “no pain” being 0 and “theworst pain imaginable” being 10. A study investigator will record thepatient's body weight and baseline vital signs. All data will berecorded on data collection sheets, including patients' sex,demographics, medical history, and vital signs, and entered into SPSS(version 24.0; IBM Corp) by the research manager. Confirmation ofwritten consent acquisition for all participants, and statisticalanalyses will be conducted by the statistician (Michael Silver), whowill work independently of any data collection.

The on-duty ED pharmacist will prepare an oral dose of ketamine by usingan injectable form for parenteral use. The on-duty ED pharmacist willprepare a syringe/medication cup containing: the combo group (Combo):325 mg and 0.5 or 1 mg/kg oral dose ketamine; oral ketamine (OK) group:matching placebo tablets and 0.5 or 1 mg/kg oral dose ketamine accordingto the predetermined randomization list, which will be created in SPSS(version 24; IBM Corp, Armonk, NY) with block randomization of every 10participants. The research associate will deliver syringes/medicationcups to the patients' nurse who will administer medication. Studyinvestigators will record pain scores and adverse effects at 30, 60, 90,and 120 minutes. If patients reported a pain numeric rating scale scoreof 5 or greater and requested additional pain relief, an oral immediaterelease morphine tablet of 7.5 mg will be given. Patients will beclosely monitored for adverse effects during the entire study period (upto 120 minutes) by study investigators. Common adverse effects that areassociated with OK are felling of unreality, dizziness, nausea,vomiting, and sedation. Common adverse effects are associated with Comboare nausea, dyspepsia, epigastric discomfort, heartburn, dizziness.

Data Analysis: Data analyses will include frequency distributions andindependent-sample t-test to assess differences in pain scores at thevarious intervals. Mixed-model linear regression will be used to comparechanges in pain numeric rating scale across time points.

For categorical outcomes (e.g., complete resolution of pain), a X² orFisher's exact test will be used to compare outcomes at 60 minutes.Based on the validation of a verbally administered rating scale of acutepain in the ED and the comparison of verbal and visual pain scales, wewill use a primary outcome consisting of a minimal clinically meaningfuldifference of 2 between two groups at the 60-minute pain assessment.

Contemplated Outcomes: The primary outcome will include a reduction ofpain scores on numeric rating pain scale (NRS) at 60 minutes mark formthe baseline. The secondary outcomes will include a need for rescueanalgesia and rates of adverse up to 120 minutes. With respect to uniqueadverse effects of SDK, we will use Side Effect Rating Scale forDissociative Anesthetics (SERSDA) and Richmond Agitation Sedation Scale(RASS) (ref) SERSDA Scale includes fatigue, dizziness, nausea, headache,feeling of unreality, changes in hearing, mood change, generaldiscomfort, and hallucinations with severity of each graded by patientson a five-point scale, with “0” representing the absence of any adverseeffects and “4” representing a severely bothersome side effect. RASSevaluates the severity of agitation and/or sedation in accordance to thenine-point scale with scores ranging from “-4” (deeply sedated) to “0”(alert and calm) to “+4” (combative).

SAE Reporting: Any serious adverse event, requiring intervention, willbe reported to the IRB within 24 hours of discovery by the researchstaff. Less serious adverse events will be reported within a week ofdiscovery. There are known expected outcomes and side effects to theprocedures and medications being received and these are the samerisks/side effects as the standard of care—these will be reported ifthey are serious and require intervention.

Timetable: The entire study (from commencement until recruitment of thelast patient) will last 12 months. The research team will monitor andrecord each patient's pain scores and adverse events. The research team,pharmacist, and research manager will be immediately aware and/ornotified if a serious adverse event occurs. The patient will be treatedappropriately by ED team of physicians and nurses, and subsequently theadverse effect report will be filed to the IRB.

EXAMPLE 3 Management of Headache

This example compares the combination of dual-route aspirin anddual-route ketamine to Rimegepant (Nurtec®, Biohaven Pharmaceuticals,New Haven, Conn.) for managing acute headache in the ED in a randomized,open-label, clinical trial.

Nurtec (Rimegepant) is an orally administered small molecule CGRPreceptor antagonist with efficacy in the acute treatment of migraine.Following oral administration of NURTEC Orally Disintegrating Tablet,rimegepant is absorbed with the maximum concentration at 1.5 hours. Theabsolute oral bioavailability of rimegepant is approximately 64%.Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent byCYP2C9. Rimegepant is primarily eliminated in unchanged form (˜77% ofthe dose) with no major metabolites (i.e., >10%) detected in plasma. Themost common adverse reaction are nausea (2% in patients who receivedNURTEC ODT compared to 0.4% of patients who received placebo).Hypersensitivity, including dyspnea and severe rash, occurred in lessthan 1% of patients treated with NURTEC ODT.

NURTEC ODT 75 mg orally disintegrating tablets are white to off-white,circular, debossed with the symbol, and supplied in cartons containing ablister pack of 8 orally disintegrating tablets. Each ODT contains 75 mgrimegepant.

This example contemplates that the administration of a combination ofdual-route aspirin and oral ketamine would provide similar analgesicefficacy to Nurtec with respect to analgesic efficacy at 60 min and 120minutes in ED patients with acute headache.

Subjects: Patients 18 years of age and older presenting to the ED withacute headache (defined as HA lasting no more than 1 week) and aninitial pain score of 5 or more on a standard 11-point (0 to 10) numericrating scale and requiring oral analgesia as determined by the treatingattending physician. Patients' screening and enrollment will beperformed by study investigators and research assistants. All patientswill be enrolled at various times of the day when study investigatorswill be available for patient enrollment and an ED pharmacist will beavailable for medication preparation.

Eligibility Criteria: Patients 18 years of age and older presenting tothe ED with acute headache (<7 days) and an initial pain score of 5 on astandard 11-point (0 to 10) numeric rating scale. Patients will have tobe awake, alert, and oriented to person, place, and time, and will beable to demonstrate understanding of the informed consent process andcontent. Patients also will have to demonstrate ability to verbalize thenature of any adverse effects they might experience as well as toexpress their pain severity by using the NRS.

Exclusion Criteria: Patients with altered mental status, allergy toaspirin/ketamine/rimegepant, pregnant patients, unstable vital signs(systolic blood pressure <90 or >180 mm Hg, pulse rate <50 or >150beats/min, and respiration rate <10 or >30 breaths/min), inability toprovide consent, consumption of Aspirin/NSAID' s within 6 hours ofarrival to the ED, or acetaminophen within 4 hours of arrival to the ED,active PUD, history of GI Hemorrhage, history of renal and hepaticinsufficiency, past medical history of alcohol or drug abuse, orschizophrenia, as well as clinical findings concerning for acuteintracranial process, acute infections process, or vascular catastrophe,pregnant patients and breastfeeding patients.

Design: This is a prospective, open-label, equivalence trial evaluatingand comparing analgesic efficacy and safety of a combination ofdual-route aspirin and oral ketamine, and Nurtec in adult patientspresenting to the ED of Maimonides Medical Center with acute headache.Upon meeting the eligibility criteria, patients will be offered toparticipate in the study.

Data Collection Procedures: Each patient will be approached by a studyinvestigator for acquisition of written informed consent and HealthInsurance Portability and Accountability Act authorization after beingevaluated by the treating emergency physician and determined to meetstudy eligibility criteria. When English will not be the participant'sprimary language, a language-appropriate consent form will be used andnon-investigator, hospital-employed, trained interpreters or licensedtelephone interpreter will assist in acquisition of informed consent.Baseline pain score will be determined with an 11-point numeric ratingscale (0 to 10), described to the patient as “no pain” being 0 and “theworst pain imaginable” being 10. A study investigator will record thepatient's body weight and baseline vital signs. All data will berecorded on data collection sheets, including patients' sex,demographics, medical history, and vital signs, and entered into SPSS(version 24.0; IBM Corp) by the research manager. Confirmation ofwritten consent acquisition for all participants, and statisticalanalyses will be conducted by the statistician (Michael Silver), whowill work independently of any data collection.

Study Set-up. The on-duty ED pharmacist will prepare medications in thefollowing fashion: the combination of dual-route aspirin (325 mg) andoral ketamine (0.85 or 1 mg/kg) (Combo) and Nurtec that are provided bythe sponsor will be placed in the medication cups according to arandomization list generated by the research manager by SPSS (version24.0; IBM Corp, Armonk, N.Y.). The oral dose of ketamine will beprepared by using an injectable form of ketamine at 0.85 or 1 mg/kg doseand matching (by volume) placebo (normal saline). This weight-based doseof ketamine and saline placebo will be placed in the syringe andsweetener will be added to offset the bitter taste of ketamine. TheCombo group will receive the combination medication cup and oralketamine syringe, and Nurtec group will receive Nurtec ODT blistercontaining 75 mg of rimegepant in the medication cup and oral placebosyringe.

The research associate will deliver both syringes and medication cups tothe patients' nurse who will administer medication. Study investigatorswill record pain scores and adverse effects at 30, 60, 90, and 120minutes. If patients reported a pain numeric rating scale score of 5 orgreater and requested additional pain relief, the rescue analgesic (s)and routes will be chosen upon treating attending's discretion. Patientswill be closely monitored for adverse effects during the entire studyperiod (up to 120 minutes) by study investigators. Common adverseeffects that are associated with oral ketamine are felling of unreality,dizziness, nausea, vomiting, and sedation. Common adverse effects thatare associated with Combo are nausea, dyspepsia, epigastric discomfort.Common adverse effect that is associated with Nurtec include nausea.

Data Analysis: Data analyses will include frequency distributions andindependent-sample t-test to assess differences in pain scores at thevarious intervals. Mixed-model linear regression will be used to comparechanges in pain numeric rating scale across time points. For categoricaloutcomes (e.g., complete resolution of pain), a X² or Fisher's exacttest will be used to compare outcomes at 60 and 120 minutes. Based onthe validation of a verbally administered rating scale of acute pain inthe ED and the comparison of verbal and visual pain scales, we will usea primary outcome consisting of a minimal clinically meaningfuldifference of 2 points between two groups at the 60-minute and120-minute pain assessment.

Contemplated Outcomes: The primary outcome will include a comparativereduction of pain scores on numeric rating pain scale (NRS) at 60minutes from the baseline. The secondary outcomes will include a needfor rescue analgesia, rates of adverse effects, and change in pain scoreup to 120 minutes.

SAE Reporting: Any serious adverse event, requiring intervention, willbe reported to the IRB within 24 hours of discovery by the researchstaff. Less serious adverse events will be reported within a week ofdiscovery. There are known expected outcomes and side effects to theprocedures and medications being received and these are the samerisks/side effects as the standard of care—these will be reported ifthey are serious and require intervention.

EXAMPLE 4 Oral VTS-K (Combination of VTS-Aspirin and Oral Ketamine) asan Adjunct to Oral Antidepressant Therapy in Treatment of MajorDepressive Disorder

This example tests the use of ketamine in treating depression. It iscontemplated that 486 mg of aspirin (dual-route intraoral/oraladministration) and 1.2 mg/kg ketamine (dual-route intraoral/oraladministration) as an adjunct to oral antidepressant treatment willresult in reduction of depressive symptoms based on the change in scorefrom baseline to day 7 after initial dose on the Montgomery-AsbergDepression Rating Scale (MADRS).

Subjects: This is a prospective observational proof of concept study ofmedically stable (based on the physical examination, history, and vitalsigns) adults patients 18 years of age and older with a diagnosis ofmajor depressive disorder without psychotic features according toDSM-IV-TR criteria presenting to the psychiatric clinic for evaluation.Patients to have a score ≥22 on the Montgomery-Asberg Depression RatingScale (MADRS) on day 1 before dosing. Participants ought to agree tocontinue oral antidepressant therapy they were receiving prior to theenrollment into the study.

Eligibility Criteria:

Adult patients with TRD with MADRS score >22 upon presentation to theclinic. Participants ought to agree to standard-of-care treatment withone or more non-investigational antidepressants.

Participants ought to agree to continue oral antidepressant therapy theywere receiving prior to the enrollment into the study. All participantsmust agree to provide and informed consent.

Exclusion Criteria:

Adult patients with recent or current suicidal ideation with an intentto act, homicidal ideations with an intent to act, intellectualdisability, major depressive disorder with psychosis, posttraumaticstress disorder, obsessive-compulsive disorder, substance use disorder,antisocial personality disorder, borderline personality disorder, or acurrent or past diagnosis of a psychotic disorder altered mental status,allergy to aspirin and ketamine, pregnant patients, unstable vital signs(systolic blood pressure <90 or>180 mm Hg, pulse rate <50 or >150beats/min, and respiration rate <10 or >30 breaths/min), consumption ofAspirin or NSAID's within 6 hours of arrival to the ED, active PUD,history of GI Hemorrhage, and history of renal and hepaticinsufficiency.

Design:

This is a prospective observational proof of concept study of adultpatients 18 years of age and older with a diagnosis of TRD withoutpsychotic features according to DSM-IV-TR criteria presenting to thepsychiatric clinic for evaluation. Eligible participants will receive486 mg of aspirin (dual-route intraoral/oral administration) and 1.2mg/kg ketamine (dual-route intraoral/oral administration) as an adjunctto oral antidepressant treatment twice a week for 1 week (on day 1 and 4for the week). All participants will be observed for 4 hours in theoutpatient setting after receiving the medication and their depressivesymptoms will be assessed at 4-hour mark by MADRS Scale and QIDS-SRscale (Quick Inventory of Depressive Symptomatology-Self Report) andtheir adverse effect related to VTS=K administration will be assessed byusing the Clinician Administered Dissociative State Scale (CADSS) andMOAA/S scale and RASS scale.

Study Set Up

The on-duty pharmacist will prepare an oral dose of ketamine by using aninjectable form for parenteral use. The on-duty ED pharmacist willprepare a syringe/medication cup containing the medication according tothe predetermined list, which will be created in SPSS (version 24; IBMCorp, Armonk, N.Y.). The oral sweetener solution of 1 ml will be addedto the syringe containing ketamine. The research pharmacist will deliversyringes/medication cup to the patients' nurse who will administermedication. Subjects will be instructed to first suck off the outerlayer of aspirin for about 30-60 seconds and then swallow the tablet.The oral antidepressant medication will be initiated or optimized forall participants on day 1. Participants taking a recently initiatedantidepressant at screening could continue the antidepressant at thesame dosage during treatment with study drug. Study investigators willrecord VS, and adverse effects at 30 minute, 60 minutes, 2 hours, and 4hours. Patients will be closely monitored for adverse effects during theentire observation period (for up to 2-4 hours) by study investigators.

Efficacy Assessments

Research associates and study investigators will assess depressivesymptom severity with the Montgomery-Åsberg Depression Rating Scale(MADRS) on day one and on day 4 and day 7 (for days 1 and 4 this willinclude pre-dose, 40 minutes, 120 minutes, and 240 minutes post-dose).Patients will also be screened using the Beck Scale for Suicide Ideationand their sense of hopelessness using the Beck Hopelessness Scale beforedosing and 4 hours after dosing on day one and pre-dosing on days 4, and7.

Safety Assessments

Vital signs will be checked before medication administration and 1, 2, 4hours post-drug administration during the study period. Adverse eventswill be monitored throughout the study. The Clinician-AdministeredDissociative States Scale (CADSS) will be administered before dosing andat 40 minutes, 2 hours, and 4 hours after dosing on day 1 and day 4. Inaddition, a Modified Observer's Alertness/Sedation Scale (MOAA/S) willbe used to assess the level of sedation.

Common adverse effects that are associated with oral ketamine arefelling of unreality, dizziness, nausea, vomiting, sedation, anddissociation. Common adverse effects are associated with VTS-Aspirin arenausea, dyspepsia, epigastric discomfort,

Data Collection Procedures: Each patient will be approached by a studyinvestigator for acquisition of written informed consent and HealthInsurance Portability and Accountability Act authorization after beingevaluated by the treating psychiatry physician and determined to meetstudy eligibility criteria. When English will not be the participant'sprimary language, a language-appropriate consent form will be used andnon-investigator, hospital-employed, trained interpreters or licensedtelephone interpreter will assist in acquisition of informed consent.Baseline Depression score via MADRS will be recorded by a studyinvestigator. All data will be recorded on data collection sheets,including patients' sex, demographics, medical history, and vital signs,and entered into SPSS (version 24.0; IBM Corp) by the research manager.Confirmation of written consent acquisition for all participants, andstatistical analyses will be conducted by the statistician who will workindependently of any data collection.

Data Analysis: Data analyses will include mixed-effect model withrepeated measures with baseline MADRS score as covariate; time bytreatment interaction as fixed effect and patient as random effect.

Expected Outcomes:

The primary outcome will include a change in depressive symptoms on theMontgomery-Asberg Depression Rating Scale (MADRS) from the baseline(pre-dose day 1) and day 7.

The secondary outcomes will include: a change in depressive symptoms onthe Montgomery-Asberg Depression Rating Scale (MADRS) from the baseline(pre-dose on day 1 and 4) and 4 hours post-medication administration.

Rates of Side effects will be reported by using theClinician-Administered Dissociative States Scale (CADSS), Side EffectRating Scale for Dissociative Anesthetics (SERSDA), and ModifiedObserver's Alertness/Sedation Scale (MOAA/S). The SERSDA scale includesfatigue, dizziness, nausea, headache, feeling of unreality, changes inhearing, mood change, general discomfort, and hallucinations withseverity of each graded by patients on a five-point scale, with “0”representing the absence of any adverse effects and “4” representing aseverely bothersome side effect.

SAE Reporting: Any serious adverse event, requiring intervention, willbe reported to the IRB within 24 hours of discovery by the researchstaff. Less serious adverse events will be reported within a week ofdiscovery. There are known expected outcomes and side effects to theprocedures and medications being received and these are the samerisks/side effects as the standard of care—these will be reported ifthey are serious and require intervention.

EXAMPLE 5 Therapeutic Effects of Dual Ketamine/Aspirin

This example presents the results from a trial as outlined in Example 1,in comparison with data collected from similar trials with other agentsand the same testing protocol and pain measurement scales, in the samemedical center by the same research team and same statistical methods.The testing agents and dosages are listed in Table 1.

TABLE 1 Agents and Doses No. Agent Dose 1 Morphine (IV) 0.1 mg/kg 2Morphine Sulfate Immediate 15 mg Release (MSIR) (oral) 3 Percocet (oral)10 mg 4 Dual route ketamine + aspirin 0.5 mg/kg ketamine (intraoral +oral) 5 Ketamine (IV) 0.3 mg/kg 6 Nebulized ketamine Mixed dose 7Ibuprofen (oral) Mixed dose 8 Ketorolac (IV)

The efficacy to reduce acute musculoskeletal pain by each agent wasmeasured as described in Example 1. The results are presented in FIG. 1.As expected, IV morphine had the highest efficacy, resulting in a5.1-point reduction of acute musculoskeletal pain. The least efficaciouswas oral ibuprofen (2 points). IV ketamine and intranasal (nebulized)ketamine were both effective, achieving a reduction of about 4 points,similar to oral morphine and Percocet.

Quite unexpectedly, the dual-route ketamine and dual-route aspirinachieved a 3.84-point reduction of acute musculoskeletal pain. Asexplained above, it has been demonstrated that the oral bioavailabilityof ketamine is about ⅕ of the availability via IV injection. Here, themeasured efficacy of dual-route ketamine (0.5 mg/kg) and aspirin (3.84points) is equivalent to that of IV ketamine (0.3 mg/kg) (3.8 points).Therefore, these data suggest that the dual-route ketamine (withaspirin) at 0.5 mg/kg is equivalent to conventional oral ketamine at 1.5mg/kg. This is a three-fold increase of efficacy as compared to theconventional oral ketamine.

A typical side effect of ketamine is sedation, which was measured with aRichmond Agitation-Sedation Scale (RASS) as described in Table 2A. Theresults are compared to published ones that either used the RASS scaleor a MOAA/S scale (Modified Observer's Assessment of Alertness/Sedation)which is described in Table 2B. The published data include those fromMotov 2017 (Motov S. et al., Ann Emerg Med. 2017 August; 70(2):177-184),Motov 2019 (Motov S. et al., Am J Emerg Med, 2019 February;37(2):220-227), and the drug label of Spravato® esketamine (intranasalketamine).

TABLE 2A Sedation Measurement Scores - RASS Score Description +4Combative +3 Very agitated +2 Agitated +1 Restless 0 Alert and calm −1Drowsy −2 Light sedation −3 Moderate sedation −4 Deep sedation −5Unarousable sedation

TABLE 2B Sedation Measurement Scores - MOAA/S Score Description 5Responds readily to name spoken in normal tone 4 Lethargic response toname spoken in normal tone 3 Responds only after name is called loudlyand/or repeatedly 2 Responds only after mild prodding or shaking 1Responds only after painful trapezius squeeze 0 No response afterpainful trapezius squeeze

The results are shown in FIG. 2, along with control data from thepublications. Only 8% patients who received the dual-route ketamine andaspirin had any sedation side effect, and only 4% reported moderate orabove sedation side effects (RASS<=−3 or MOAA/S<=3). Such rates areconsiderably lower than both IV ketamine and intranasal ketamine. Giventhat the dual-route ketamine and aspirin was as efficacious as IV andintranasal ketamine, its greatly reduced sedation side effect was trulya surprise.

Another common side effect of ketamine is dissociation, which wasmeasured with a Side Effects Rating Scale of Dissociative Anesthetics(SERSDA) scale as described in Table 3A. The results are compared topublished ones that either used the SERSDA scale or aClinician-Administrated Dissociative States Scale (CADSS) which isdescribed in Table 3B. The published data include those from Motov 2017,Motov 2019, and the drug label of Spravato® esketamine (intranasalketamine).

TABLE 3A Dissociation Measurement Scale - SERSDA Score Description 0 Nochange 1 Weak 2 Modest 3 Bothersome 4 Very Bothersome

TABLE 2B Dissociation Measurement Scale - CADSS 27 questions 0-4 pointseach >4 increase “positive”

The results are shown in FIG. 3, along with control data from thepublications. Only 4% patients who received the dual-route ketamine andaspirin had any dissociation side effect (SERSDA Unreality; *CADSS >4 ptincurrence), and none (0%) reported significant dissociation sideeffects (SERSDA Unreality: Bothersome +; *CADSS >10 pt incurrence). Suchrates are considerably lower than both IV ketamine and intranasalketamine. Given that the dual-route ketamine and aspirin was asefficacious as IV and intranasal ketamine, its greatly reduceddissociation side effect was again truly a surprise.

EXAMPLE 6

This example provides the results of additional clinical testing ofvarious compositions of the instant disclosure, in terms of their painreduction efficacy and associated adverse effects.

This new study was an extension of the study in Example 5, at the samesite, also with patients with acute musculoskeletal pain in the ER(e.g., acute back pain, or a wrist fracture). The tested formulationsare described below.

In a first analysis, data collected from only patients having fractureswere analyzed. They were divided into an aspirin/ketamine (Any ASA/KET)group (N=11) and a dual-route (intraoral and oral) ketamine (Dual RouteKET) group (N=4). Primarily, the safety endpoint was examined defined asany SERSDA scores of 3 or higher (i.e., moderately or severely“bothersome”). As shown in FIG. 4, none of the patients that receivedboth aspirin and ketamine (Any ASA/KET) had any moderate or severeadverse events, while 25% of the patients receiving dual-route ketamine(Dual Route KET) had adverse events.

The aspirin/ketamine group was further divided, into a dual routeaspirin +dual route ketamine (Dual Route A/K) arm and an oral aspirin+oral ketamine (Oral A/K) arm. In this comparison, all adverse events ofSERSDA2+were examined. As shown in FIG. 5, the Oral A/T arm hadsignificantly higher (65% more) SERSDA2+ events than the Dual Route A/Karm.

In the second analysis, also only with patients having fractures,patients with any combination of ASA/KET (Any ASA/KET) were compared topatients that received dual-route (intraoral and oral) ketamine (DualRoute KET). As shown in FIG. 6, the pain reduction efficacy of theASA/KET combination was about 36% higher than the Dual Route KET arm.When the ASA/KET group was divided into two subgroups (i.e., Dual RouteA/K and oral aspirin+oral ketamine (Oral A/K)), both subgroupsoutperformed dual-route ketamine (FIG. 7).

In the third analysis, patients that received oral aspirin and oralketamine (Oral A/K, N=25) were compared to those who received Dual RouteA/K (N=10). None of the patients experienced SERSDA3+. The comparison ofSERSDA2+0l events is shown in FIG. 8, which shows that 65% more ASA/KETpatients had adverse events than Dual Route A/K patients.

In terms of pain reduction, Dual Route A/K patients had 42% more painreduction, 3.84 vs. 2.7, as shown in FIG. 9. Also, in terms of time toonset (50% of pain reduction), the Dual Route A/K arm experienced muchquicker pain relief, 23 minutes vs. 60 minutes, as shown FIG. 10.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

1. A method for administering ketamine to a subject or treating pain inthe subject, comprising administering to the subject (a) a firstcomposition comprising a first amount of ketamine and (b) a secondcomposition comprising a second amount of ketamine, wherein the firstcomposition disintegrates or dissolves intraorally providing rapidrelease of the ketamine of the first composition, and the secondcomposition is ingested and released in the gastrointestinal track ofthe subject.
 2. The method of claim 1, wherein the first compositioncomprises at least about 20% of the therapeutically effective amount ofketamine and the second composition comprises at least about 20% of thetherapeutically effective amount of ketamine.
 3. The method of claim 1,wherein the first composition further comprises a first amount ofaspirin.
 4. The method of claim 3, wherein the second compositionfurther comprises a second amount of aspirin.
 5. The method of claim 1,wherein the first composition and the second composition are provided inthe form of a tablet or capsule.
 6. The method of claim 5, wherein thesecond composition is enclosed within the first composition.
 7. Themethod of claim 6, wherein the first composition is chewable.
 8. Themethod of claim 7, wherein the second composition is compressed.
 9. Themethod of claim 8, wherein the second composition comprises entericcoating.
 10. The method of claim 1, wherein the pain is acutemusculoskeletal pain.